Depression to Dementia


  • (i) Individuals who develop depression at any point in their lives, sustain minimal or no depression-related neuropathology (eg, glucocorticoid neurotoxicity), and who have stable, normal cognitive functioning;
  • (ii) Individuals who develop depression at any point and who experience depression-related neuropathology that results in MCI that is stable (unless they experience additional depressive episodes);
  • (iii) Individuals who accumulate AD neuropathology over many years and who develop late-life depression (related or unrelated to AD pathology), that lowers brain reserve capacity, and results in expression of MCI earlier than otherwise would be the case, and given the underlying neuropathology, progress to AD;
  • (iv) Individuals who accumulate AD neuropathology over many years along with co-occurring cerebrovascular disease, which damages the frontostriatal circuitry, leading to late-life depression. The total neuropathologic burden, combined with depressed mood, lowers brain reserve capacity, leads to expression of MCI (eg, memory and executive dysfunction) earlier than otherwise would be the case, and, given the underlying neuropathology, progresses to AD along with co-occurring cerebrovascular disease;
  • and (v) Individuals who develop cerebrovascular disease (with variable neuropathologic burden), that damages the frontostriatal circuitry, leading to late-life depression and MCI (eg, executive dysfunction), that, will follow the course of the underlying cerebrovascular disease.
AD Alzheimer’s disease
CAD coronary artery disease
HPA hypothalamic-pituitary-adrenal
MCI mild cognitive impairment
MDE major depressive episode
WMH hyperintense white matter regions

ad-depGlucocorticoids contribute to hippocainpal atrophy and learning/episodic memory impairment

Depression is associated with neuroendocrine changes similar to those observed in animal models of chronic stress, including abnormalities within the hypothalamicpituitary-adrenal (HPA) axis. Most notably, depressed subjects have been shown to exhibit, increased HPA central drive with elevated corticotrophin-releasing hormone (CRH) and vasopressin production by cells of the hypothalamic paraventricular nucleus (PVN); impaired negative feedback regulation due to decreased expression of corticosteroid receptors in the hypothalamus and pituitary as well as upstream CNS regulatory centers; and adrenal hypertrophy (reviewed in ref 25). The net effect of these changes in HPA function is chronic elevation of adrenal glucocorticoid production with impaired negative feedback and abnormal homeostatic regulation. Such HPA dysregulation is clinically detectable (via dexamethasone nonsuppression or elevated 24-hour urinary Cortisol) in about, half of patients with major depression.2526 HPA dysregulation may be more common among older depressed individuals, as suggested by the finding of a significant correlation between age and post-dexamethasone Cortisol levels in individuals with late-life depression.27

Adrenal glucocorticoid/cortisol regulates HPA activity through both direct, negative feedback at the pituitary and hypothalamus and indirect, mechanisms involving higher central nervous system (CNS) centers. The human hippocampus, for example, contains large numbers of corticosteroid receptors and plays a critical role in downregulating CRH release via a multisynaptic pathway terminating in y-aminobutyric acid (GABA)-ergic output to the paraventricular nucleus (reviewed in ref 28). At. the same time, HPA disturbances causing prolonged hypercortisolemia may promote hippocampal atrophy and functional decline, such that HPA regulation is further compromised. ‘Iliis interaction may underlie the observed association between hypercortisolemic disease states such as Cushing’s syndrome and depression, and both hippocampal atrophy and impairment, in the verbal and spatial memory functions subserved by the hippocampus.29,30

Animal studies suggest that high-stress conditions or exogenous glucocorticoids can cause hippocampal neuronal damage31 and memory impairment.32 These changes have been observed concurrent with stress or exogenous glucocorticoid administration, and appear to progress over a lifetime of stress or glucocorticoid excess (see review in ref 33). Human studies in older adults likewise suggest that hippocampal size and function are diminished in the setting of elevated glucocorticoids,3435 and in proplemiaortion to duration of prior hypercortisolemia.36

On the basis of these findings, many have hypothesized that glucocorticoids may promote hippocampal cell injury and death when chronically elevated, as in the setting of hypercortisolemica associated with major depression. Glucocorticoid-induced cellular damage may be mediated through effects on several biochemical substrates. Postulated mechanisms include decreased glucose uptake and ATP generation, elevated intracellular calcium with increased free radical production and degradative enzyme activity, and impaired uptake of glutamate from hippocampal synapses resulting in excitotoxicity.28,37 In addition, hypercortisolemia has been linked to a decrease in neurogenesis in the dentate gyrus.38 While the combination of cell death and decreased neurogenesis may theoretically contribute to hippocampal cell loss over time, recent, evidence suggests at. most a minor role for this mechanism in hypercortisolcmic human subjects in the absence of cooccurring insults.39 Animal and human studies support the idea that glucocorticoids contribute to hippocampal atrophy and functional deficits predominantly through more subtle alterations, including reduced synapse number,40 atrophy of pyramidal cell dendrites,41derangement, of glial cells,42 and other changes.

The loss of hippocampal volume and memory function observed in some elders with late -life depression suggests the possibility that depression may be a predispositional risk factor for AD in particular. Indeed, lower hippocampal volumes independently predict subsequent AD in groups of MCI and cognitively normal elderly subjects.52 Likewise, deficits in verbal learning and memory, similar to those described in cuthymic patients with history of major depression,30 also predict AD (eg, ref 53). While a primary causal role for depression in AD pathogenesis seems unlikely, depression-associated hypercortisolemia leading to decline in hippocampal size, connectivity and cognitive function may represent one of multiple links between depression and dementia as described below.

Brain and cognitive reserve are often used interchangeably, but in fact, have subtle but. distinct differences in meaning.119 Nevertheless, either may account, equally well for the relationship between depression and dementia. Tltic concept of brain reserve capacity, first proposed by Satz120 varies across individuals such that those with greater neuronal redundancy are able to tolerate more cell loss than those with less redundancy, before manifesting clinical symptoms. The concept of redundancy refers to the notion that, circuits contain more than the minimum number of neurons needed to perform an operation. Redundancy is evident when individuals incur substantial neuronal loss before the appearance of clinical symptoms. Thus, brain reserve capacity posits that individual differences in neural redundancy translate into differences in thresholds for vulnerability to or protection from clinical symptoms after brain damage. The concept of cognitive reserve developed by Stern (eg, refs 121 ,122) is similar but rather than being based on differences in brain size or neuronal count, emphasizes differences in the efficiency or manner in which tasks are performed or information is processed.

Both brain reserve and cognitive reserve explain the role of risk and protective factors for cognitive impairment (including progressive decline into dementia), associated with brain damage. For example, higher educational attainment, larger head size, larger brain volume,123 social engagement, 124 physical activity,125 and leisure cognitive activity126,127 may result in greater redundancy and/or efficiency and therefore reserve, thereby offering protection against exhibiting clinical symptoms of dementia. Similarly, lower levels of these protective factors may reduce neuronal or functional redundancy leading to earlier dementia symptom onset for a given level of CNS damage.

While certain mechanisms may alter an individual’s risk to develop (or change the rate of development of) ADrelated pathology (eg, P-amyloid deposition), other mechanisms alter the strength of association between these biological changes and the time to develop clinical disease. We propose that depression alters an individual’s risk of cognitive dysfunction, shortening the latent period between the development, of AD neuropathology and the onset, of clinical dementia, thus increasing the incidence and prevalence of AD among older adults with depression.

About Glucocorticoids

Glucocorticoids (GCs) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor (GR),[1] that is present in almost every vertebrate animal cell. The name glucocorticoid (glucose + cortex + steroid) is composed from its role in regulation of glucose metabolism, synthesis in the adrenal cortex, and its steroidal structure (see structure to the right). A less common synonym is glucocorticosteroid.

GCs are part of the feedback mechanism in the immune system which reduces certain aspects of immune function, such as reduction of inflammation. They are therefore used in medicine to treat diseases caused by an overactive immune system, such as allergies, asthma, autoimmune diseases, and sepsis. GCs have many diverse (pleiotropic) effects, including potentially harmful side effects, and as a result are rarely sold over the counter.[2] They also interfere with some of the abnormal mechanisms in cancer cells, so they are used in high doses to treat cancer. This includes: inhibitory effects on lymphocyte proliferation as in the treatment of lymphomas and leukemias; and the mitigation of side effects of anticancer drugs.

GCs affect cells by binding to the glucocorticoid receptor (GR). The activated GR complex, in turn, up-regulates the expression of anti-inflammatory proteins in the nucleus (a process known as transactivation) and represses the expression of proinflammatory proteins in the cytosol by preventing the translocation of other transcription factors from the cytosol into the nucleus (transrepression).[2]

Glucocorticoids are distinguished from mineralocorticoids and sex steroids by their specific receptors, target cells, and effects. In technical terms, “corticosteroid” refers to both glucocorticoids and mineralocorticoids (as both are mimics of hormones produced by the adrenal cortex), but is often used as a synonym for “glucocorticoid.” Glucocorticoids are chiefly produced in the zona fasciculata of the adrenal cortex, whereas mineralocorticoids are synthesized in the zona glomerulosa.

Cortisol (or hydrocortisone) is the most important human glucocorticoid. It is essential for life, and it regulates or supports a variety of important cardiovascular, metabolic, immunologic, and homeostatic functions. Various synthetic glucocorticoids are available; these are used either as replacement therapy in glucocorticoid deficiency or to suppress the immune system.

Mitochondrial function between the heart and skeletal muscles and biomarkers of Heart Failure

Heart failure (HF) is a chronic and devastating illness becoming an increasingly important burden on the health care system. Reduced exercise tolerance is an independent predictor of hospital readmission and mortality in patients with HF [1], and is thought to be a therapeutic target [2]. Although central factors such as ejection fraction (EF) or cardiac output do play a role, peripheral factors which include reduced skeletal muscle, an alteration in fiber type to one with less oxidative properties, and decreased ATP production, are mainly responsible for the reduction in exercise capacity [3]. From these findings, mitochondrial function is thought to be an important factor in the skeletal muscle in HF patients.

We recently reported that the retention of Technetium-99m sestamibi (99mTc-MIBI) correlated inversely with mitochondrial function in vivo and ex vivo in various organs [4]. 99mTc-MIBI is a lipophilic cation used for the clinical diagnosis of coronary artery disease. 99mTc-MIBI is transported to the myocardium via coronary blood flow, where it is rapidly incorporated into myocardial cells by diffusion, and binds to mitochondria [[4], [5]]. In clinical settings, the MIBI washout rate increased if mitochondrial dysfunction was present in HF patients [6]. Moreover, we and other groups demonstrated that mitochondrial functional assessment by 99mTc-MIBI was not organ-specific including the skeletal muscle [[4], [7], [8]].

To gain insight into the mechanisms underlying exercise intolerance in HF, we analyzed 99mTc-MIBI washout of the heart and leg muscles along with other clinical and cardiopulmonary exercise (CPX) parameters.

We studied 45 consecutive hospitalized patients with CHF treated for acute decompensation. CHF was defined by the Framingham criteria. Written informed consent was obtained from all patients, and the study conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Institutional Review Board of Kitano Hospital. The exclusion criteria consisted of Killip class IV HF at the time of the study, acute myocardial infarction, and no consent. Echocardiographic data, levels of brain natriuretic peptide (BNP), the estimated glomerular filtration rate, C-reactive protein levels, and medical history were analyzed. A dose of 740 MBq (20 mCi) of 99mTc-MIBI was administered intravenously under resting conditions after an overnight fast. Planar images followed by single photon emission computed tomography images were obtained 20 min and 3 h after the injection for the calculation of the washout rate (Supplementary materials) [6].

All data are expressed as the mean ± standard deviation (SD). Differences between groups were compared using the Mann–Whitney U-test. The correlation analysis was carried out using the Pearson’s product-moment. A multiple general linear model in Poisson distribution by the likelihood-ratio chi-square test was used when the determinants of parameters were analyzed. In all tests, a value of p < 0.05 was considered significant.

Patient characteristics were as follows: 62% were male; 37% had dilated cardiomyopathy; 55% had hypertension; 24% had diabetes; the mean age was 68 years; the mean EF was 41%; the mean BNP level was 370 pg/mL; and the mean washout rate of the heart and the leg muscles was 46% and 30%, respectively. See details in Supplementary Table 1.

Fig. 1A and B show multiple scatter plots and correlation coefficient, respectively, of the variables. The 99mTc-MIBI washout of the heart and BNP and the washout of the heart and leg muscles were focused in Fig. 1C and D, respectively. A higher washout rate represents mitochondrial dysfunction. The washout rate of the heart inversely correlated to BNP level increase (Fig. 1C). 99mTc-MIBI washout rate of the heart positively correlated with the washout rate of the leg muscles (Fig. 1D), but not with left ventricular EF (Fig. 1A, pink circle). In multivariate regression analyses (Supplementary Table 2), the 99mTc-MIBI washout rate of the leg muscle and BNP levels were the factors that determined the washout rate of the heart.

Thumbnail image of Fig. 1. Opens large image

Fig. 1

Association between the MIBI washout rate of the heart and leg muscles (A). Multiple scatter plots of the variables. A red circle focused in panel C. A purple circle focused in panel D. A pink circle indicated the relationship between 99mTc-MIBI washout rate of the heart and left ventricular ejection fraction. (B) Pearson’s correlation coefficient. (C) BNP levels and 99mTc-MIBI washout rate of the heart and (D) 99mTc-MIBI washout rate of the heart and leg muscles. Line, linear correlation with standard deviation.

We analyzed data obtained from 22 patients who underwent CPX. Patients who underwent CPX were younger, but the other parameters were not significantly different from those who did not undergo CPX (Supplementary Fig. 2 and Table 3). PeakVO2 was negatively correlated with the 99mTc-MIBI washout of the leg muscles and weakly positively correlated with the length of the circumflex of the thigh (Fig. 2A ). Fig. 2B shows the relationship between peak oxygen consumption and 99mTc-MIBI washout of the leg muscles. Determinants of peak oxygen consumption in the subgroup were the 99mTc-MIBI washout of the leg and EF. Multi-collinearity was observed between the 99mTc-MIBI washout of the heart and leg muscles and the length of the circumflex of the thigh (Supplementary Table 4).

Thumbnail image of Fig. 2. Opens large image

Fig. 2

Association between the CPX parameters and the MIBI washout rate of the heart and leg muscles (A). Multiple scatter plots of the variables. (B) Peak oxygen consumption and 99mTc-MIBI washout rate of the leg muscles. Line, linear correlation with standard deviation.

The factors linking the heart and the leg muscle are currently unknown. Mechanisms involving sympathetic neural activation; cellular metabolism in the cardiac and skeletal muscles; inter-organ relationships such as anemia, chronic kidney disease, liver congestion, and depression; and inflammatory cytokines may contribute to the linkage between mitochondrial function of the heart and peripheral muscles in HF patients [9]. Brain-derived neurotrophic factor is involved in depression and is decreased in HF patients. It regulates skeletal muscle energy metabolism and is one of the linking factor candidates [10].

Muscle mass (i.e., circumflex of the thigh), in addition to the mitochondrial function of the legs, is the deciding factor for exercise capacity. In fact, a reduction in mitochondrial function and the inability to utilize oxygen delivered, i.e. low peripheral O2 extraction may contribute to the reduction in oxidative capacity. Thus, possible targets for exercise interventions to improve exercise intolerance in HF are not only the muscle’s mass but also the quality of the skeletal muscle [3].

There are several limitations. First, CPX was not done in all patients, and there were no CPX values in healthy controls. Second, we could not assess other markers of mitochondrial function or morphology of the heart and skeletal muscles as such analysis requires biopsy samples, which is beyond the scope of the study.

In summary, we demonstrated a clear correlation of mitochondrial function between the heart and skeletal muscles and biomarkers of HF.

Our results indicate that mitochondrial function of the leg muscle, along with the muscle volume, may limit exercise capacity in patients with CHF.

The Emergence of a New Dopamine Hypothesis of Schizophrenia

Summary: A collection of studies offers new insight into the role dopamine plays in schizophrenia.

Source: Elsevier.

Biological Psychiatry presents a special issue, “The Dopamine Hypothesis of Schizophrenia”, dedicated to recent advances in understanding the role of dopamine signaling in schizophrenia. The issue, organized by Anissa Abi-Dargham, MD, of Stony Brook University, New York, and a deputy editor of Biological Psychiatry, compiles seven reviews that summarize current knowledge and provide new insights.

The dopamine hypothesis of schizophrenia has been revised numerous times since clinical observations first implicated the neurotransmitter decades ago, and dopamine alterations are some of the most well-established research findings in schizophrenia.

“Unlike any other neurobiological hypothesis of the disease, the dopamine hypothesis has confirmatory evidence from in vivo studies in patients and from pharmacological therapies,” Abi-Dargham said. Despite this, researchers have yet to fully understand when and how dopamine alterations arise in the brain, or their relationship with the diversity of symptoms in the disease.

“This issue highlights the complexity of the findings in patients with the disorder, and raises the possibility that dopamine alterations can lead to a vast array of consequences on the circuitry, on learning and behavior that can explain the vast array of symptom clusters,” Abi-Dargham said.

The body of work collated in the issue ranges from human studies to animal models. Neuroimaging, genetic, and molecular imaging studies have helped elucidate the regional differences of dopamine dysfunction throughout the brain, and detailed timing of dopamine alterations in relation to development, symptom onset, and other neurobiological alterations in the disease. Animal models have allowed researchers to further refine and test the hypothesis, and explore mechanisms behind the dysregulation.

Image shows the structure of the dopamine molecule.

Clarifying the role of dopamine signaling in schizophrenia also shows promise for improving treatment for the disorder. “We include here some examples of exciting new targeted therapeutic approaches that are currently under development,” Abi-Dargham said.

Although the dopamine system has long been pegged as the culprit for psychotic symptoms in schizophrenia, a review in this issue using a computational approach to integrate experimental findings provides an explanation for how dopamine dysfunction could lead to the range of symptoms present in the disorder.

The therapeutic approaches proposed in the issue aim to find new strategies for targeting dopamine signaling to improve the limitations of current antipsychotic drugs, which only treat psychotic symptoms and come with a host of major side effects, by targeting new pathways and tapping into dopamine’s role in other regions of the brain.


Source: Rhiannon Bugno – Elsevier
Image Source: image is in the public domain.
Original Research: The special issue is “Dopamine Hypothesis of Schizophrenia,” Biological Psychiatry, volume 81, issue 1 (2017).

Elsevier “The Emergence of a New Dopamine Hypothesis of Schizophrenia.” NeuroscienceNews. NeuroscienceNews, 30 January 2017.

This Is Your Brain on Legal Cannabis

Summary: While marijuana can initially help with symptoms of anxiety and depression, it can be detrimental to mental health when used long term, a new study reports.

Source: Colorado State University.

For those suffering depression or anxiety, using cannabis for relief may not be the long-term answer.

That’s according to new research from a team at Colorado State University seeking scientific clarity on how cannabis – particularly chronic, heavy use – affects neurological activity, including the processing of emotions.

Researchers led by Lucy Troup, assistant professor in the Department of Psychology, have published a study in PeerJ describing their findings from an in-depth, questionnaire-based analysis of 178 college-aged, legal users of cannabis. Recreational cannabis became legal in Colorado in 2014. Since then, seven other states have enacted legalization for recreational use, while many others allow medical use.

“One thing we wanted to focus on was the significance of Colorado, the first state to legalize recreational cannabis, and its own unique population and use that occurs here,” Troup said.

Through the study, which was based solely upon self-reported use of the drug, the researchers sought to draw correlations between depressive or anxious symptoms and cannabis consumption.

They found that those respondents categorized with subclinical depression, who reported using the drug to treat their depressive symptoms, scored lower on their anxiety symptoms than on their depressive symptoms ­- so, they were actually more depressed than they were anxious. The same was true for self-reported anxiety sufferers: they were found to be more anxious than they were depressed.

In other words, “if they were using cannabis for self-medication, it wasn’t doing what they thought it was doing,” explained co-author Jacob Braunwalder, a recently graduated student researcher in Troup’s lab.

Study co-author Jeremy Andrzejewski led the development of the questionnaire, called R-CUE (Recreational Cannabis Use Evaluation), that took a deep dive into users’ habits, including questions about whether users smoked the drug, or consumed stronger products like hash oils or edibles. The researchers are particularly motivated to study biochemical and neurological reactions from higher-tetrahydracannabinol (THC) products available in the legal market, which can be up to 80-90 percent THC.

The researchers are quick to point out that their analysis does not say that cannabis causes depression or anxiety, nor that it cures it. But it underscores the need for further study around how the brain is affected by the drug, in light of legalization, and by some accounts, more widespread use in Colorado since legalization.

For example, said Andrzejewski, “there is a common perception that cannabis relieves anxiety.” Yet research has yet to support this claim fully, he said.

Graduate student and co-author Robert Torrence pointed to past research that shows that chronic use reduces naturally occurring endocannabinoids in the brain, which are known to play a role physiological processes including mood and memory.

Image shows a marijuana plant.

“There is research to suggest that cannabis can help with anxiety and depression in the beginning, but it has the reverse effect later on,” said Torrence, a U.S. Army veteran who is especially interested in studying cannabis’ effectiveness in treating post-traumatic stress disorders.

Due to the federal government’s stringent regulations around researching cannabis, which is a schedule I drug, the general public’s perception of how it affects the brain is often based in “mythos,” Braunwalder said. “We want to add more information to the entire body of research.”

There are currently no CSU research labs that administer cannabis to study participants, as administration of the drug for research would require special licensing and security.

Moving forward, the researchers want to refine their results and concentrate on respondents’ level and length of exposure to legally available high-THC products like concentrates and hash oils, around which there has been little scientific inquiry.

“It is important not to demonize cannabis, but also not to glorify it,” Troup said. “What we want to do is study it, and understand what it does. That’s what drives us.”


Source: Anne Manning – Colorado State University
Image Source: image is in the public domain.
Original Research: Full open access research for “The relationship between cannabis use and measures of anxiety and depression in a sample of college campus cannabis users and non-users post state legalization in Colorado” by Lucy J. Troup, Jeremy A. Andrzejewski, Jacob T. Braunwalder, and Robert D. Torrence in PeerJ. Published online December 8 2016 doi:10.7717/peerj.2782


The relationship between cannabis use and measures of anxiety and depression in a sample of college campus cannabis users and non-users post state legalization in Colorado

As part of an ongoing research program into the relationship between cannabis use and emotion processing, participants were assessed on their level of cannabis exposure using the Recreational Cannabis Use Examination, a measure developed specifically to assess cannabis use in Colorado post state legalization. Three groups were created based on self-reported use: a control group who have never used, a casual user group and a chronic user group. Each participant also completed two measures of mood assessment, the Center for Epidemiologic Studies Depression Scale and the State-Trait Anxiety Inventory. Relationships between cannabis use groups and scores on these measures were then analyzed using both correlations and multivariate analysis of variance. Results indicate a relationship between casual cannabis use and scoring highly for depressive symptomatology on the Center for Epidemiologic Studies Depression Scale. There were no significant relationships between cannabis use and scores on the State-Trait Anxiety Inventory.

“The relationship between cannabis use and measures of anxiety and depression in a sample of college campus cannabis users and non-users post state legalization in Colorado” by Lucy J. Troup, Jeremy A. Andrzejewski, Jacob T. Braunwalder, and Robert D. Torrence in PeerJ. Published online December 8 2016 doi:10.7717/peerj.2782

How Depression May Compound Risk of Type 2 Diabetes

Depression, metabolic factors combine to boost risk of developing diabetes, study finds.

Depression may compound the risk of developing type 2 diabetes in people with such early warning signs of metabolic disease as obesity, high blood pressure and unhealthy cholesterol levels, according to researchers from McGill University, l’Université de Montréal, the Institut de recherches cliniques de Montréal and the University of Calgary.

While previous studies have pointed to a link between depression and diabetes, the new findings, published in the journal Molecular Psychiatry, suggest that when depression combines with metabolic risk factors the risk of developing diabetes rises to a level beyond the sum of its parts.

“Emerging evidence suggests that not depression, per se, but depression in combination with behavioral and metabolic risk factors increases the risk of developing type 2 diabetes and cardiovascular conditions,” said lead author Norbert Schmitz, an Associate Professor in McGill’s Department of Psychiatry and a researcher at its affiliated Douglas Mental Health University Institute. “The aim of our study was to evaluate characteristics of individuals with both depressive symptoms and metabolic risk factors.”

Over 2,500 adults studied

The four-and-a-half year study divided 2,525 participants in Quebec, aged between 40 and 69, into four groups: those with both depression and three or more metabolic risk factors; two groups, each with one of these conditions but not the other; and a reference group with neither condition.

In a departure from previous findings, the researchers discovered that participants with depression, alone, were not at significantly greater risk of developing diabetes than those in the reference group. The group with metabolic symptoms but not depression was around four times more likely to develop diabetes. Those with both depression and metabolic risk factors, on the other hand, were more than six times more likely to develop diabetes, with the analysis showing the combined effect of depression and metabolic symptoms was greater than the sum of the individual effects.

A vicious cycle?

The researchers believe depression, metabolic symptoms and the risk of developing diabetes interact in a number of ways. In some cases, a vicious cycle may emerge with depression and metabolic risk factors aggravating one another.

Evidence shows people suffering from depression are less likely to adhere to medical advice aimed at tackling metabolic symptoms, whether it be taking medication, quitting smoking, getting more exercise or eating a healthier diet. Without effective management, metabolic symptoms often worsen and this can in turn exacerbate the symptoms of depression.

woman looking depressed.

Beyond these behavioral aspects, some forms of depression are associated with changes in the body’s metabolic systems which can lead to weight gain, high blood pressure and problems with glucose metabolism. Meanwhile, some antidepressant medications can also cause weight gain.

Integrated treatment key to prevention

The researchers emphasize that not all cases of depression are the same – only some people with depression also suffer from metabolic problems. When it comes to improving health outcomes, identifying those patients who suffer from both depression and metabolic symptoms as a subgroup and adopting an integrated treatment approach may be crucial to breaking the cycle.

“Focussing on depression alone might not change lifestyle/metabolic factors, so people are still at an increased risk of developing poor health outcomes, which in turn increases the risk of developing recurrent depression,” Prof. Schmitz said.


This research was supported by the Canadian Institutes of Health Research (CIHR), and the Fonds de recherche du Québec – Santé, Canada.

Source: Katherine Gombay – McGill University
Image Credit: The image is in the public domain.
Original Research: Abstract for “Depression and risk of type 2 diabetes: the potential role of metabolic factors” by N Schmitz, S S Deschênes, R J Burns, K J Smith, A Lesage, I Strychar, R Rabasa-Lhoret, C Freitas, E Graham, P Awadalla and J L Wang in Molecular Psychiatry. Published online February 23 2016 doi:10.1038/mp.2016.7


Depression and risk of type 2 diabetes: the potential role of metabolic factors

The aim of the present study was to evaluate the interaction between depressive symptoms and metabolic dysregulations as risk factors for type 2 diabetes. The sample comprised of 2525 adults who participated in a baseline and a follow-up assessment over a 4.5-year period in the Emotional Health and Wellbeing Study (EMHS) in Quebec, Canada. A two-way stratified sampling design was used, on the basis of the presence of depressive symptoms and metabolic dysregulation (obesity, elevated blood sugar, high blood pressure, high levels of triglycerides and decreased high-density lipoprotein). A total of 87 (3.5%) individuals developed diabetes. Participants with both depressive symptoms and metabolic dysregulation had the highest risk of diabetes (adjusted odds ratio=6.61, 95% confidence interval (CI): 4.86–9.01), compared with those without depressive symptoms and metabolic dysregulation (reference group). The risk of diabetes in individuals with depressive symptoms and without metabolic dysregulation did not differ from the reference group (adjusted odds ratio=1.28, 95% CI: 0.81–2.03), whereas the adjusted odds ratio for those with metabolic dysregulation and without depressive symptoms was 4.40 (95% CI: 3.42–5.67). The Synergy Index (SI=1.52; 95% CI: 1.07–2.17) suggested that the combined effect of depressive symptoms and metabolic dysregulation was greater than the sum of individual effects. An interaction between depression and metabolic dysregulation was also suggested by a structural equation model. Our study highlights the interaction between depressive symptoms and metabolic dysregulation as a risk factor for type 2 diabetes. Early identification, monitoring and a comprehensive management approach of both conditions might be an important diabetes prevention strategy.

“Depression and risk of type 2 diabetes: the potential role of metabolic factors” by N Schmitz, S S Deschênes, R J Burns, K J Smith, A Lesage, I Strychar, R Rabasa-Lhoret, C Freitas, E Graham, P Awadalla and J L Wang in Molecular Psychiatry. Published online February 23 2016 doi:10.1038/mp.2016.7

Depression, Folate, SAMe and serotonin


S-Adenosylmethionine (SAMe) is a naturally-occurring compound found in almost every tissue and fluid in the body. It is involved in many important processes. SAMe plays a role in the immune system, maintains cell membranes, and helps produce and break down brain chemicals, such as serotonin, melatonin, and dopamine. It works with vitamin B12 and folate (vitamin B9). Being deficient in either vitamin B12 or folate may reduce levels of SAMe in your body.

Several studies show that SAMe helps relieve the pain of osteoarthritis. Other studies suggest that SAMe may help treat depression. Researchers have also examined SAMe’s use in the treatment of fibromyalgia and liver disease with mixed results. Many of the early studies used SAMe given intravenously or as an injection. Only recently have researchers been able to look at the effects of SAMe taken by mouth.


Some research suggests that SAMe is more effective than placebo in treating mild-to-moderate depression and is just as effective as antidepressant medications without the side effects (headaches, sleeplessness, and sexual dysfunction). In addition, antidepressants tend to take 6 to 8 weeks to begin working, while SAMe seems to begin more quickly. Researchers are not sure how SAMe works to relieve depression. But they speculate it might increase the amount of serotonin in the brain just as some antidepressants do.

Many studies have examined injectable forms of SAMe, not oral supplements. More research is needed to determine whether SAMe works for depression. Because serious depression is a dangerous illness, you should seek help from your doctor before taking SAMe or any supplement.


A number of well-designed studies show that SAMe may reduce pain and inflammation in the joints, and researchers think it may promote cartilage repair. In several short-term studies (ranging from 4 to 12 weeks), SAMe supplements were as effective as nonsteroidal anti-inflammatory drugs (NSAIDs, such as ibuprofen and naproxen) in adults with knee, hip, or spine osteoarthritis, in lessening morning stiffness, reducing pain and swelling, improving range of motion, and increasing walking pace. Several studies also suggest that SAMe has fewer side effects than NSAIDs. Another study compared SAMe to celecoxib (Celebrex), a type of NSAID called a COX-2 inhibitor, and found that over time SAMe was as effective as celecoxib in relieving pain. Other studies show no differences in pain relief or tolerability between treatment with SAMe or habumetone over 8 weeks in people with knee osteoporosis.


SAMe can be effective in reducing symptoms of fibromyalgia, including pain, fatigue, morning stiffness, and depressed mood. But most studies used an injectable form of SAMe. Among studies that examined doses of SAMe by mouth, some found it was effective at reducing these symptoms while others found no benefit.

Liver disease

People with liver disease often cannot synthesize SAMe in their bodies. Preliminary studies suggest that taking SAMe may help treat chronic liver disease caused by medications or alcoholism. A study of 123 men and women with alcoholic liver cirrhosis (liver failure) found that SAMe treatment for 2 years improved survival rates and delayed the need for liver transplants better than placebo. Other studies show that SAMe may help normalize levels of liver enzymes in people with liver disease. Studies in mice show that SAMe protects against and can also reverse liver damage. However, these studies have been small and of short duration. Larger and longer studies are needed to confirm these findings.


Preliminary evidence suggests that SAMe may improve cognitive symptoms, such as the ability to recall information and remember words. Researchers suspect SAMe acts on regions of the brain that regulate gene expression of amyloid proteins, one of the hallmarks of Alzheimer disease.


Some studies suggest SAMe can effectively inhibit cancer tumor cells. Other studies suggest that taking the drug levodopa (L-dopa) for Parkinson disease may lower the levels of SAMe in the body, which may contribute to depression and increase the side effects of L-dopa. However, researchers have also found evidence that taking SAMe may make L-dopa less effective. If you have Parkinson disease, do not take SAMe without talking to your doctor first.

Dietary Sources

SAMe is not found in food. It is produced by the body from the amino acid methionine and ATP which serves as the major energy source for cells throughout the body.

Available Forms

SAMe is available in tablets or capsules, which are more stable and may be more dependable in terms of the amount of SAMe in the pill. They should be stored in a cool, dry place, but not refrigerated. Tablets should be kept in the blister pack until you take them.

How to Take It

Starting with a low dose (for example, 200 mg per day) and increasing slowly helps avoid stomach upset.

It is important to note that many of the studies of SAMe have tested injectable, not oral, forms. It is not as clear whether taking SAMe orally is as reliable or effective. Small studies suggest that oral supplementation with SAMe is not well absorbed by the body. Clinicians recommend taking oral SAMe with vitamin B12, folic acid, methionine, and trimethylglycine to enhance absorption.


SAMe should never be given to a child without your doctor’s supervision.


Recommended doses of SAMe vary depending on the health condition being treated. The following list gives information on the dosages used in studies for each condition:

  • Depression. 800 to 1,600 mg of SAMe per day, in 2 divided doses (morning and afternoon).
  • Osteoarthritis. 600 to 1,200 mg per day in 2 to 3 divided doses.
  • Fibromyalgia. A dosage of 400 mg, 2 times per day for 6 weeks.
  • Alcoholic liver disease. 600 to 1,200 mg per day by mouth in divided doses for 6 months enhances liver function. For liver disease, a qualified health care provider should supervise administration of SAMe.


Because of the potential for side effects and interactions with medications, you should take dietary supplements only under the supervision of a knowledgeable health care provider.

Side effects may include dry mouth, nausea, gas, diarrhea, headache, anxiety, a feeling of elation, restlessness, and insomnia. Sweating, dizziness, and palpitations have also been reported. For this reason, you should not take SAMe at night.

Large doses of SAMe may cause mania (abnormally elevated mood). Start at a low dose and gradually increase it. DO NOT exceed recommended doses.

Pregnant and breastfeeding women should not take SAMe.

People with bipolar disorder (manic depression) should not take SAMe since it may worsen manic episodes.

SAMe should not be combined with other antidepressants without first consulting your doctor.

People taking SAMe may want to take a multivitamin that contains folic acid and vitamins B12 and B6.

Possible Interactions

If you are being treated with any of the following medications, you should not use SAMe without first talking to your health care provider.

Taking SAMe at the same time as these drugs may increase the risk of serotonin syndrome (a potentially dangerous condition caused by having too much serotonin in your body):

  • Dextromethorphan (Robitussin DM, other cough syrups)
  • Meperidine (Demerol)
  • Pentazocine (Talwin)
  • Tramadol (Ultram)

Antidepressant medications

SAMe may interact with antidepressant medications, increasing the potential for side effects including headache, irregular or accelerated heart rate, anxiety, and restlessness, as well as the potential fatal condition called Serotonin Syndrome, mentioned above. Some experts theorize that taking SAMe increases the levels of serotonin in the brain, and many antidepressants do the same. The concern is that combining the two may increase serotonin to dangerous levels. Talk to your doctor before using SAMe if you are taking any medications for depression or anxiety.

Levodopa (L-dopa)

SAMe may reduce the effectiveness of this medication for Parkinson disease.

Medications for diabetes

SAMe may reduce levels of blood sugar and may strengthen the effect of diabetes medications, which increases the risk of hypoglycemia (low blood sugar).


Serotonin (/ˌsɛrəˈtnn, ˌsɪərə/[6][7][8]) or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Biochemically derived from tryptophan,[9] serotonin is primarily found in the gastrointestinal tract (GI tract), blood platelets, and the central nervous system (CNS) of animals, including humans. It is popularly thought to be a contributor to feelings of well-being and happiness.[10]

Approximately 90% of the human body‘s total serotonin is located in the enterochromaffin cells in the GI tract, where it is used to regulate intestinal movements.[11][12] The serotonin is secreted luminally and basolaterally which leads to increased serotonin uptake by circulating platelets and activation after stimulation, which gives increased stimulation of myenteric neurons and gastrointestinal motility.[13] The remainder is synthesized in serotonergic neurons of the CNS, where it has various functions. These include the regulation of mood, appetite, and sleep. Serotonin also has some cognitive functions, including memory and learning. Modulation of serotonin at synapses is thought to be a major action of several classes of pharmacological antidepressants.

Serotonin secreted from the enterochromaffin cells eventually finds its way out of tissues into the blood. There, it is actively taken up by blood platelets, which store it. When the platelets bind to a clot, they release serotonin, where it serves as a vasoconstrictor and helps to regulate hemostasis and blood clotting. Serotonin also is a growth factor for some types of cells, which may give it a role in wound healing. There are various serotonin receptors.

Serotonin is metabolized mainly to 5-HIAA, chiefly by the liver. Metabolism involves first oxidation by monoamine oxidase to the corresponding aldehyde. This is followed by oxidation by aldehyde dehydrogenase to 5-HIAA, the indole acetic acid derivative. The latter is then excreted by the kidneys.

In addition to animals, serotonin is found in fungi and plants.[14] Serotonin’s presence in insect venoms and plant spines serves to cause pain, which is a side-effect of serotonin injection.[citation needed] Serotonin is produced by pathogenic amoebae,[citation needed] and its effect on the gut[specify] causes diarrhea.[citation needed] Its widespread presence in many seeds and fruits may serve to stimulate the digestive tract into expelling the seeds.

Folate Deficiency Signs and Symptoms

Loss of appetite and weight loss can occur. Additional signs are weakness, sore tongue, headaches, heart palpitations, irritability, and behavioral disorders.[3] In adults, anemia (macrocytic, megaloblastic anemia) can be a sign of advanced folate deficiency.

In infants and children, folate deficiency can slow growth rate. Women with folate deficiency who become pregnant are more likely to give birth to low birth weightpremature infants, and infants with neural tube defects.

Late studies suggested an involvement in tumorogenesis (especially in colon) through demethylation/hypomethylation of fast replicating tissues.

Some of the symptoms can also result from a variety of medical conditions other than folate deficiency. It is important to have a physician evaluate these symptoms so that appropriate medical care can be given.


Studies suggest that folate and vitamin B12 status may play a role in depression.[4] The role of vitamin B12 and folate in depression is due to their role in transmethylation reactions, which are crucial for the formation of neurotransmitters (e.g. serotonin, epinephrine, nicotinamides, purines, phospholipids).[4][5]

Low levels of folate or vitamin B12 can disrupt transmethylation reaction, leading to an accumulation of homocysteine (hyperhomocisteinemia) and to impaired metabolism of neurotransmitters (especially the hydroxylation of dopamine and serotonin from tyrosine and tryptophan), phospholipids, myelin, and receptors. High homocysteine levels in the blood can lead to vascular injuries by oxidative mechanisms which can contribute to cerebral dysfunction. All of these can lead to the development of various disorders, including depression.[4][5]

Low plasma B12 and low plasma folate has been found in studies of depressive patients. Furthermore, some studies have shown that low folate levels are linked to a poor response of antidepressant treatment, and other studies also suggest that a high vitamin B12 status may be associated with better treatment outcomes. Therefore, not only does adequate consumption of these two vitamins help decrease the risks of developing depression, but they can also help in the treatment of depression when antidepressant drugs are used

Yogic Breathing Helps Fight Major Depression

Summary: According to researchers, a yogic breathing technique could help those with major depressive disorder who did not fully respond to antidepressant therapies.

Source: University of Pennsylvania.

Controlled breathing practices show promise in patients who don’t fully respond to antidepressants.

A breathing-based meditation practice known as Sudarshan Kriya yoga helped alleviate severe depression in people who did not fully respond to antidepressant treatments, reports a new study published today in the Journal of Clinical Psychiatryfrom researchers in the Perelman School of Medicine at the University of Pennsylvania. The study bolsters the science behind the use of controlled yogic breathing to help battle depression.

In a randomized, controlled pilot study, led by Anup Sharma, MD, PhD, a Neuropsychiatry research fellow in the department of Psychiatry at Penn, researchers found significant improvement in symptoms of depression and anxiety in medicated patients with major depressive disorder (MDD) who participated in the breathing technique compared to medicated patients who did not partake. After two months, the yoga group cut its mean Hamilton Depression Rating Scale (HDRS) score by several points, while the control group showed no improvements. HDRS is the most widely used clinician-administered depression assessment that scores mood, interest in activities, energy, suicidal thoughts, and feelings of guilt, among other symptoms.

More than half of the 41 million Americans who take antidepressants do not fully respond. Add-on therapies are often prescribed to enhance the effects of the drugs in these patients, but they typically offer limited additional benefits and come with side effects that can curb use, prolonging the depressive episode. What’s more, patients who don’t fully respond to antidepressants are especially at risk of relapse.

“With such a large portion of patients who do not fully respond to antidepressants, it’s important we find new avenues that work best for each person to beat their depression,” Sharma said. “Here, we have a promising, lower-cost therapy that could potentially serve as an effective, non-drug approach for patients battling this disease.”

The meditation technique, which is practiced in both a group setting and at home, includes a series of sequential, rhythm-specific breathing exercises that bring people into a deep, restful, and meditative state: slow and calm breaths alternated with fast and stimulating breaths.

“Sudarshan Kriya yoga gives people an active method to experience a deep meditative state that’s easy to learn and incorporate in diverse settings,” Sharma said.

In past studies, the practice has demonstrated a positive response in patients with milder forms of depression, depression due to alcohol dependence, and in patients with MDD; however, there are no clinical studies investigating its use for depression in an outpatient setting. Past studies suggest that yoga and other controlled breathing techniques can potentially adjust the nervous system to reduce stress hormones. Overall, the authors also note, well-designed studies that evaluate the benefits of yoga to treat depression are lacking, despite increased interest in the ancient Indian practice. Millions of Americans participate in some form of yoga every year.

Image shows a woman in a yoga pose.

In the study, researchers enrolled 25 patients suffering from MDD who were depressed, despite more than eight weeks of antidepressant medication treatment. The medicated patients were randomized to either the breathing intervention group or the “waitlist” control group for eight weeks. (The waitlist group was offered the yoga intervention after the study). During the first week, participants completed a six-session program, which featured Sudarshan Kriya yoga in addition to yoga postures, sitting meditation, and stress education. For weeks two through eight, participants attended weekly Sudarshan Kriya yoga follow-up sessions and completed a home practice version of the technique.

Patients in the Sudarshan Kriya yoga group showed a significantly greater improvement in HDRS scores compared to patients in the waitlist group. With a mean baseline HDRS score of 22.0 (indicating severe depression at the beginning of the study), the group that completed the breathing technique for the full two months improved scores by 10.27 points on average, compared to the waitlist group, which showed no improvements. Patients in the yoga group also showed significant mean reductions in total scores of the self-reported Beck Depression (15.48 point improvement) and Beck Anxiety Inventories (5.19 point improvement), versus the waitlist control group.

Results of the pilot study suggest the feasibility and promise of Sudarshan Kriya as an add-on intervention for MDD patients who have not responded to antidepressants, the authors wrote. “The next step in this research is to conduct a larger study evaluating how this intervention impacts brain structure and function in patients who have major depression,” Sharma said.


Penn co-authors include Marna S. Barrett, PhD, Andrew J. Cucchiara, PhD, Nalaka S. Gooneratne, MD, and senior author Michael E. Thase, MD.

Funding: The work was supported by grants from the American Psychiatric Association/Substance Abuse and Mental Health Services Administration Minority Fellowship Program, Indo-American Psychiatric Association, and the National Center for Advancing Translational Sciences of the National Institutes of Health (UL1TR000003).

Source: Johanna Harvey – University of Pennsylvania
Image Source: This image is in the public domain.
Original Research: The study will appear in Journal of Clinical Psychiatry during the week of November 21 2016.